Taxanes are a family of compounds that includes paclitaxel, a cytotoxic natural product, and docetaxel, a semi-synthetic derivative, two compounds that are widely used in the treatment of cancer, E. Baloglu and D. G. I. Kingston, J. Nat. Prod. 62: 1448-1472 (1999). Taxanes are mitotic spindle poisons that inhibit the depolymerization of tubulin, resulting in cell death. While docetaxel and paclitaxel are useful agents in the treatment of cancer; their antitumor activity is limited because of their non-specific toxicity towards normal cells. These off target associations can cause complications ranging from inflammation to the death of the patient.
Due to the particular insolubility of taxanes, pharmaceutical forms have been difficult to formulate. For example, TAXOL® (Bristol-Myers Squibb) utilizes a formulation containing paclitaxel dissolved in Cremophor® EL (a polyethoxylated castor oil) and ethanol, as a delivery agent. However, Cremophor® EL has been called a dose limiting agent because of its toxicities. In particular, the Cremophor® EL vehicle can have serious side effects including severe hypersensitivity reactions. ABRAXANE® (Abraxis BioScience, LLC) utilizes a human blood albumin-bound nanoparticulate form of paclitaxel, thereby eliminating Cremophor® EL. However, while such nanoparticles may bond to and internalize to tumor cells via gp60 endothelial cell surface receptors, they are not specifically targeted to tumor cells.
A common approach to target therapeutics specifically to cancer cells is to conjugate anti-cancer agents to antibodies or functional fragments. However, antibody therapy may result in significant levels of non-specific cellular association. The serum iron transport protein transferrin (Tf) has been investigated as a potential drug carrier. Conjugation of anticancer agents to Tf allows for specific targeting to cancer cells, since the transferrin receptor (TfR) is overexpressed in a broad range of cancers (Cazzola et al., Blood. 1990; 75(10):1903-19; Reizenstein, Med Oncol Tumor Pharmacother. 1991; 8(4):229-33). Specific targeting of drugs to cancer cells with Tf may help alleviate nonspecific toxicity associated with chemotherapy and radiation treatments (Saul et al., J Control Release. 2006; 114(3):277-87; Kreitman, Aaps J. 2006; 8(3):E532-51). Tf conjugates of cytotoxins including methotrexate (MTX), artemisinin, and diphtheria toxin (DT) have been reported, as well as Tf conjugates with novel payloads such as liposomally encapsulated drugs and siRNA (Lim and Shen, Pharm Res. 2004; 21(11): 1985-92; Lai et al., Life Sci. 2005; 76(11): 1267-79; Johnson et al., J Biol Chem. 1988; 263(3): 1295-300; Hu-Lieskovan et al., Cancer Res. 2005; 65(19): 8984-92; Tros et al., J Drug Target. 2006; 14(8):527-35; Maruyama et al., J Control Release. 2004; 98(2):195-207; Chin et al., J Control Release. 2006; 112(2):199-207).
Several chemotherapeutic agents may be bound to transferrin via available lysine residues using a glutaraldehyde reaction to form a chemical linking group. The glutaraldehyde can be used to activate the chemotherapeutic agent either when the agent and transferrin are in solution together or the chemotherapeutic agent can be activated and then mixed in solution with the transferrin. Paclitaxel has been bound via glutaraldehyde reaction to Transferrin; see, for example, U.S. Pat. Nos. 6,825,166; and 7,417,023; and U.S. Patent Application No. 20090181048. However, such glutaraldehyde linkages can inhibit or prevent release of the chemotherapeutic upon cellular uptake.